Roflumilast (Daliresp)an FDA approved oral medication for moderate to severe COPD--has been shown to improve insulin sensitivity and body weight. It is unknown whether its effect on insulin sensitivity is mediated by weight loss or through other mechanisms. Adults with overweight/obesity and prediabetes received roflumilast for six weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation and mitochondria function. Food intake and physical activity were also assessed. Our primary outcome was the change in the results of hyper-insulinemic euglycemic clamp. We did not observe improvement in our primary outcome although our study was underpowered. Roflumilast decreased food intake and visceral adiposity and increased basal hepatic gluconeogenesis. Inflammatory and adhesion markers, though unchanged, were associated with one another and with incretin hormones only after roflumilast. We also observed significant associations among roflumilast-induced changes in incretin hormones, adipocytokines, peripheral insulin sensitivity and adiposity. Short term roflumilast has a caloric-restriction effect in adults with prediabetes and overweight/obesity. With known benefits of caloric restriction, the potential for using roflumilast to treat obesity- and aging-associated metabolic diseases needs further study.